The benefits of decreasing the particle sizes of pharmaceutical compounds are well known. Commonly referred to as micronizing, the reduction in the particle sizes of pharmaceutical compounds has brought about improvements in dissolution profiles as well as more convenient methods of delivery. The more common techniques for the micronization of pharmaceutical compounds with Dense Gas (DG) technology include the Rapid Expansion of Supercritical Solutions (RESS) process, the Gas Anti-solvent (GAS) process, the Aerosol Solvent Extraction System (ASES) process and, more recently, the Depressurization of an Expanded Liquid Organic Solvent (DELOS) process. Carbon dioxide (CO2) is a commonly used DG, due in part to its vast abundance and ease of applicability. While the RESS and DELOS processes utilize dense or supercritical CO2 as a solvent and/or co-solvent for pharmaceutical compound processing, the GAS and ASES processes exploit the anti-solvent effect of condensed CO2 in organic solutions containing pharmaceutical compounds.
Key features of these processes are outlined below.    GAS: A volume of solution containing dissolved pharmaceutical compound(s) or working solution is introduced into a sealed vessel at atmospheric pressure. Antisolvent is then introduced into the vessel from the bottom through a sparger. The working solution is expanded and precipitation of previously dissolved compounds occurs. The precipitate is rinsed by passing carbon dioxide (CO2) from the top of the vessel.    ASES: The ASES process is also known as the Supercritical Anti-solvent System (SAS). Another process that is technically similar to the ASES process is the Solution Enhanced Dispersion by Supercritical Fluids (SEDS). In ASES, working solution is physically pumped at constant flowrate into a vessel containing antisolvent through a capillary nozzle (micron size range). The flowrate of the working solution is typically in the region of 0.1 to 4 ml/min. Different nozzle configurations exist where the working solution is introduced cocurrent to antisolvent, the nozzle is energized with ultrasound etc. With SEDS, the working solution is introduced coaxially with anti-solvent to effect better mixing between the two. After delivery, e.g. spraying, of the working solution, the precipitate is rinsed with CO2 to remove residual solvent.    DELOS: Working solution is introduced into a sealed vessel and is next partially expanded with CO2, similar to the GAS process but without precipitation occurring. Expanded solution is then slowly depressurized over a valve into another vessel under isobaric conditions. Precipitation occurs following depressurization as a result of critical cooling of the expanded working solution as CO2 flashes. The precipitate is rinsed by passing CO2 or nitrogen at low pressure.    RESS: RESS is technically different to the processes described above. RESS uses supercritical fluids as the primary solvent to dissolve the pharmaceutical compound. Organic solvents are added (if any) in very small amounts to modify/increase the solubility of the pharmaceutical compound in supercritical carbon dioxide. Thus pharmaceutical compounds are loaded into a sealed vessel mounted with a frit at the exit to prevent entrainment of solid pharmaceutical compounds out of the vessel. The vessel is pressurized with supercritical fluid to operating conditions capable of dissolving the pharmaceutical compound. When necessary, organic solutions (co-solvents) may be is added to modify and increase the solubility of the pharmaceutical compound into the supercritical phase. After saturating the supercritical carbon dioxide with the pharmaceutical compound, the supercritical fluid is depressurized into another vessel through a capillary nozzle to a much lower pressure. Depressurization of the supercritical fluid causes a dramatic decrease in its solvating power and the precipitation of previously dissolved pharmaceutical compounds is effected. Precipitate is retained in the second vessel typically with a filter.
Several crystallization techniques, such as SEDS and SAS use capillary nozzles and low flowrates (0.1 to 4 ml/min) to atomize working solutions for precipitation. Such low delivery rates of working solutions make for very long and tedious processing. Existing SCF (supercritical fluid) recrystallization techniques introduce antisolvent to a working solution or vice versa gradually in eluted amounts, leading to the formation of concentration gradients. As a result, secondary nucleation and crystal growth occur at different rates depending on localized concentrations. This may lead to broad particle size distributions and inconsistent results.
Prior art processes are often difficult to scale up from laboratory scale to production scale, due to scaling factors with nozzles, flow rates etc. Exact working solution/anti-solvent ratios are also often difficult, if not impossible to establish. Some of the above processes require quite complex equipment, resulting in additional equipment expense. Existing processes commonly prove difficult to scale-up because capillary nozzle spray patterns as a function of increased working solution flowrates are difficult to predict (ASES/SAS). Also, these processes require complicated design of critical equipment, for example geometrical extrapolation of nozzle design with SEDS. Capillary nozzles used in existing processes are prone to clogging and the formation of a precipitate at the nozzle tip interferes with working solution atomization. Additionally, existing processes operate with concentration gradients existing in the precipitation chamber. Scaling up equipment of these processes would alter the position and nature of these concentration gradients.